Conserved cysteines in titin sustain the mechanical function of cardiomyocytes

Elias Herrero-GalanFernando DominguezInes Martinez-MartinCristina Sanchez-GonzalezNatalia VicenteLaura LalagunaElena Bonzon-KulichenkoEnrique CalvoEsther Gonzalez-LopezMarta Cobo-MarcosBelen BornsteinAna BricenoJuan Pablo OchoaJose Maria Garcia-AznarCarmen Suay-CorrederaMaria Rosaria PricoloAngel Fernandez-TrasancosDiana Velazquez-CarrerasClaudio Badia CareagaBelen PradosFrancisco Gutierrez-AgueraMahmoud AbdellatifSimon SedejPeter P RainerDavid GigantiGiovanna GiovinazzoJuan A. BernalRaul Perez-JimenezTorsten Bloch RasmussenThomas Morris HeyInmaculada Vivo-OrtegaJesus Piqueras-FloresEnrique Lara-PezziJesus VazquezPablo Garcia-Pavia, Jorge Alegre-Cebollada

Abstract: The protein titin determines cardiomyocyte contraction and truncating variants in the titin gene (TTN) are the most common cause of dilated cardiomyopathy (DCM). Different to truncations, missense variants in TTN are currently classified as variants of uncertain significance due to their high frequency in the population and the absence of functional annotation. Here, we report the regulatory role of conserved, mechanically active titin cysteines, which, contrary to current views, we uncover to be reversibly oxidized in basal conditions leading to isoform- and force-dependent modulation of titin stiffness and dynamics. Building on our functional studies, we demonstrate that missense mutations targeting a conserved titin cysteine alter myocyte contractile function and cause DCM in humans. Our findings have a direct impact on genetic counselling in clinical practice.

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